Xu et al.

Nutr Metab (Lond) (2021) 18:46

https://doi.org/10.1186/s12986-021-00563-2

REVIEW Open Access

The relationship of different levels

of high iodine and goiter in school children:
a meta‑analysis
Tingting Xu, Zhiyuan Ren, Shaohan Li, Long Tan* and Wanqi Zhang

Abstract
Background: Over the past decade, the phenomenon of high urine iodine (HUI) and high water iodine (HWI) has
become more common. But the risk of goiter caused by different levels of HUI and HWI remains unclear.
Objectives: To explore the risk of goiter development caused by HUI and HWI, and compare the risk of goiter devel-
opment from different levels of high iodine.
Methods: The Medline, Cochrane library, Embase, China National Knowledge Infrastructure and Wan fang databases
were searched for relevant population-based studies investigating the link between high iodine levels and goiter
development in mainland China. Three reviewers extracted data from the included studies independently, assessing
the prevalence of goiter development due to high iodine.
Results: Taking 100 μg/L ≤ UIC < 300 μg/L (UIC = urinary iodine concentration) as the reference group, the odds
ratio (OR) regarding high iodine levels and goiter formation was 1.74 (95% CI 1.50, 2.01, P < 0.001), if the water iodine
concentration (WIC) was greater than 100 μg/L, the OR between goiter development and WIC was 4.74 (95% CI 1.15,
19.46, P = 0.001). The Linear trend analysis of HUI and goiter showed that the prevalence of goiter increased with the
increase of UIC (χ2 = 734.605, P < 0.001).
Conclusions: When the UIC ≥ 300 μg/L or the WIC ≥ 100 μg/L, the risk of goiter will increase. The higher the UIC, the
greater the risk of goiter development. In order to improve the public thyroid health, we should adhere to the moni-
toring of urinary iodine and water iodine, and keep them at an appropriate level.
Trial registration: PROSPEROCR, CRD42020197620. Registered 8 August 2020, https://​www.​crd.​york.​ac.​uk/​PROSP​
ERO/.
Keywords: High urinary iodine, High water iodine, Goiter, School children, Meta-analysis

Introduction promoting material and energy metabolism and allowing

Iodine is an essential trace element in the human body
and is a crucial component of both thyroxin and triiodo-
thyronine, key hormones produced by the thyroid. Iodine
exerts its physiological function through these hormones,
*Correspondence: tanlong@tmu.edu.cn
Department of Nutrition and Food Hygiene, School of Public Health,
Tianjin Medical University, Heping District, No. 22, Qixiangtai Road, Tianjin,
China
growth and development. Insufficient iodine intake can
lead to an iodine deficiency, which in turn will manifest
itself as specific health problems such as goiter develop-
ment or endemic cretinism [1, 2]. The adopted global
strategy of universal salt iodization has begun to com-
bat iodine deficiencies and has significantly improved
the health of the global population [3]. However, iodine
intake must be kept in balance; excessive iodine lev-
els will lead to adverse effects just as insufficient iodine

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Xu et al. Nutr Metab (Lond) (2021) 18:46
levels will. An excessive iodine intake can lead to thyroid
dysfunction; this can cause multiple health conditions
including: hypothyroidism, hyperthyroidism, autoim-
mune thyroiditis and goiter formation [4, 5].
High iodine levels can be caused by dietary intake, with
food high in iodine and iodized salt proving problematic;
high background levels of iodine in drinking water may
also cause this and exacerbate the problem of a high die-
tary intake. Both the WHO and the Chinese government
recommended monitoring goiter rates in children as an
indicator for long-term iodine nutrition in the popula-
tion [6]. When iodine exposure is high, it is thought that
the prevalence of children with goiters will exceed 5%. A
cross-sectional survey of areas with high levels of iodine
in the water was conducted in northern China; it was
found that in area where water iodine levels exceeded
than 300 μg/L, the population’s urinary iodine concentra-
tion (UIC) was on average 476.3 μg/L, with a goiter prev-
alence of 10% [7]. It was also shown that when iodized
table salt was consumed in areas with high iodine level
water (iodine salt concentration of 10.4–34.1 mg/kg), the
average UIC increased to 518 μg/L and the prevalence of
goiters was 32.96% [8].
However, the risk of goiter development caused by dif-
ferent levels of high iodine intake was still unclear. There-
fore, the aim of this study was to clarify the risk of high
iodine intake on goiter development. It also aimed to
evaluate the relationship between different high urinary
iodine levels (HUI) and high water iodine (HWI) and the
prevalence of goiters in these populations, using a meta-
analysis approach.
Materials and methods
The review was registered in the PROSPERO Inter-
national Prospective Register of Systematic Reviews
(https://​www.​crd.​york.​ac.​uk/​prosp​ero; CRD number:
42020197620).
Literature search
Medline, Embase, Cochrane library, China National
Knowledge Infrastructure (CNKI) and Wan Fang data-
bases were searched by computer from database incep-
tion to March 2020. The reference list generated was then
manually searched. The Medline, Embase and Cochrane
library database searches used the following search
terms: ((’Iodine’ OR ’iodide’) AND ’excess’ OR ’high’
OR ’excessive’) AND ’goiter’. The search terms (“high or
excess” and “iodine” and “goiter” (in Chinese)) were used
to search the CNKI and Wan Fang databases.
Inclusion and exclusion criteria
HUI level was defined in accordance with the standards
of the WHO/UNICEF/ICCIDD [9] and HWI level was
Page 2 of 9
defined in accordance with the standards of GB19380-
2016 [10]. The defined standard of HUI used 300 μg/L
UIC as cut-off value for school-age children and adults;
the standard for HWI level was defined as 100 μg /L
water iodine concentration (WIC). Therefore, the follow-
ing studies were included in this meta-analysis (Fig. 1):
(1) cross-sectional studies that defined a high iodine
intake group using a UIC cut-off of 300 μg/L for school-
age children, with controls selected from populations
with average or slightly elevated intakes (cut-off values
for average and slightly elevated iodine intakes were 100–
200 μg/L and 200–300 μg/L UIC in school-age children,
respectively); (2) cross-sectional studies that defined the
group of areas with high water iodine levels using a WIC
cut-off of 100 μg/L, whereas the controls were selected
from populations with normal water iodine levels ( Nor-
mal water iodine levels were ≤ 100 μg/L in WIC). In
cases of repeated publication, only the first published
article was included. Only articles published in English or
Chinese were considered. Animal studies, case reports,
reviews, studies not reporting sample size and studies
with incomplete data, were all excluded.
Data extraction and quality evaluation
Data was independently extracted by three authors from
the included studies (Li SH, Ren ZY and Xu TT). When
the results from the literature were uncertain, it was dis-
cussed between the authors before reaching a final agree-
ment. The following data were extracted from included
literatures: surname of first author, publish time, study
time, UIC, WIC, the number of patients with goiters,
Fig. 1 A flow chart of the literature search used for this meta-analysis
Xu et al. Nutr Metab (Lond) (2021) 18:46
total number of researchers and the prevalence of goiters.
The methodological quality of the included studies was
assessed using the cross-sectional study evaluation scale
recommended by the Agency for Healthcare Research
and Quality (AHRQ) [11]. There were 11 criteria to this
scale. Each criterion included three options: “yes”, “no”
and “unclear”. A “yes” scored 1 point whereas “unclear”
or “no” scored 0 points. Article quality was assessed as
follows: low quality = 0–3; moderate quality = 4–7; high
quality = 8–11. The evaluation results of the 11 studies
included in the meta-analysis are shown in Table 1. This
assessment was performed by 2 authors (Li SH and Ren
ZY) independently, with a third author (Xu TT) being
consulted to settle disagreements.
Statistical analysis
Stata software 16.0 and RevMan 5.3 were used to perform
the meta-analysis. The odds ratio (OR) and 95% con-
fidence interval (CI) were the statistical effect size used
to estimate the effect of iodine exposure. A P < 0.05 was
considered statistically significant. The ­I2 test was used to
quantify heterogeneity [12]. According to the Cochrane
Handbook for Systematic Reviews [13], if the I­ 2 value was
less than 50%, the heterogeneity could be accepted, and
the fixed-effects model was used. If high levels of het-
erogeneity ­(I2 > 50%) were detected between the studies,
the random-effects model was selected. If different sub-
groups of the same group required different models, the
random-effects model was used. The presence of publica-
tion bias was examined using the Begg’s test [14], P > 0.1
was considered statistically significant. The subgroup
analyses of the prevalence of goiter with different HUI
and the prevalence of goiter with different HWI would be
done. Mantel Haenszel χ2 test was used for linear trend
analysis of HI and goiter.
Results
Literature search and the characteristics of the included
studies
During the initial database search, 5847 articles were
retrieved. Following an initial screening based on the
paper title and abstract, 222 articles were retrieved and
screened for full text reading. Of the 222 papers, 183
were found irrelevant, 3 had incomplete data, 22 did not
have a controlled design and 4 did not examine school
age children. Consequently, 10 studies were included in
the meta-analysis [15–24] (Fig. 1). The characteristics of
these studies are listed in Table 1.
High urinary iodine and goiter
The association between HUI and the prevalence of
goiters is shown in Fig. 2. A UIC of 100–300 μg/L was
selected as the reference group. 7 articles reported the
Page 3 of 9
prevalence of goiters, which included 16 studies. These
16 studies included 104,645 subjects. There were 49,244
subjects from the UIC ≥ 300 μg/L group and 55,401
subjects from the 100–300 μg/L group. The OR value
was 1.74 (95% CI 1.50, 2.01, P < 0.001). It indicated that
a UIC ≥ 300 μg/L was associated with an increased risk
of developing a goiter compared to a UIC from 100–
300 μg/L. The result of the Begg’s test and Egger’s test
were P = 0.163 > 0.1, indicating that there was no signif-
icant publication bias.
High water iodine and goiter
The association between HWI (> 100 μg/L) and the
development of goiters was shown in Fig. 3. Three arti-
cles reported the development of goiters. These stud-
ies included 879 subjects (632 subjects from the high
iodine group and 247 subjects from the control group).
None of the studies crossed the invalid line. The OR
value was 4.74 (95% CI 1.15, 19.46, P = 0.008). This
indicated that a WIC > 100 μg/L was associated with
an increased risk of goiter development compared with
WI ≤ 100 μg/L. Owing to the limited number of studies
included in this aspect of the analysis, publication bias
was not assessed.
Subgroup analysis
Prevalence of goiter with different high urinary iodine levels
The associations between different levels of HUI and
the prevalence of goiters were shown in Fig. 4. Tak-
ing a UIC of 100–300 μg/L as the reference group, the
risk of goiter development was assessed in groups with
a UIC of 300–500 μg/L, 500–800 μg/L, 800–1000 μg/L
and ≥ 1000 μg/L. The OR values were 1.67 (95% CI 1.42,
1.97, P < 0.001), 1.78 (95% CI 1.57, 2.00, P < 0.001), 2.13
(95% CI 1.56, 2.91, P < 0.001) and 2.11 (95% CI 1.40, 3.18,
P < 0.001), respectively. The overall risk of high iodine
causing goiter development was OR = 1.84 (95% CI 1.63,
2.07, P < 0.001).
Linear trend analysis of high iodine and goiter
Linear trend analysis of HUI and goiter
The linear-by-linear association between different levels
of HUI and the prevalence of goiter are shown in Table 2.
The urine iodine concentration was divided into five
groups from low to high as follows: 100–300, 300–500,
500–800, 800–1000, ≥ 1000μg/L for Mantel Haenszel
χ2 test. The result showed that there was a linear cor-
relation between the UIC and the prevalence of goiter
(χ2 = 734.605, P < 0.001). And with the increase of UIC,
the prevalence of goiter also increased.
Xu et al. Nutr Metab (Lond) (2021) 18:46 Page 4 of 9

Table 1 The characteristics of 14 cross-sectional studies

Author Publish time Study time UIC (μg/L) WIC (mg/L) n N Prevalence of Quality
goiter evaluation

Liu [15] 2010 1999 13.2 – 12 82 14.6 7

37.3 – 20 379 5.2
77.7 – 89 1015 8.8
125.5 – 84 1193 7.0
174.3 – 78 1329 5.9
248.1 – 199 2731 7.3
378.0 – 350 3682 9.5
599.1 – 237 2026 11.7
865.3 – 44 364 12.2
1157.5 – 14 183 7.5
2002 13.6 – 14 108 13.0
36.2 – 14 297 4.7
77.3 – 47 876 5.4
125.7 – 48 1225 3.9
174.7 – 57 1321 4.3
245.2 – 135 2322 5.8
371.0 – 140 2160 6.5
547.7 – 48 650 7.4
862.2 – 11 86 12.9
1274.4 – 3 56 6.0
2005 10.6 – 19 172 11.0
36.0 – 33 426 7.7
77.7 – 62 1109 5.6
125.9 – 64 1392 4.6
175.8 – 72 1503 4.8
251.8 – 130 3012 4.3
368.1 – 141 2476 5.7
574.8 – 39 703 5.5
868.0 – 2 77 2.6
1200.0 – 7 69 10.1
2005 11.3 – 1 53 1.9
37.2 – 5 126 4.0
76.5 – 22 386 5.7
127.5 – 39 662 5.9
175.2 – 47 783 6.0
252.2 – 142 1824 7.8
393.8 – 452 3895 11.6
762.0 – 359 2621 13.7
868.0 – 114 675 16.9
1200.0 – 273 1531 17.8
2007 13.2 – 237 2419 9.8
46.2 – 807 6612 12.2
81.0 – 786 9251 8.5
124.4 – 548 7205 7.6
154.6 – 454 6401 7.1
244.5 – 832 10,274 8.1
357.2 – 764 8129 9.4
575.4 – 195 1623 12.0
875.6 – 11 96 11.5
1273.4 – 13 77 16.9
Xu et al. Nutr Metab (Lond) (2021) 18:46 Page 5 of 9

Table 1 (continued)
Author Publish time Study time UIC (μg/L) WIC (mg/L) n N Prevalence of Quality
goiter evaluation

Wang [16] 2015 2012 271.0 – 11 291 3.8 7

692.6 – 28 300 9.3

Xiao [17] 2011 2007 319.2 – 61 731 8.3 7
189.8 – 69 1248 5.5
Jia [18] 2014 2014 74.3 73.8 11 196 5.6 7
312.8 144.7 25 189 13.2
455.6 258.5 20 158 12.6
793.5 501.0 18 165 10.9
Wang [19] 2015 2014 514.0 304.4 9 100 9.0 7
196.17 141.6 1 100 1.0
Yu [20] 2008 1999 83.5 – 192 2708 7.1 10
242.9 – 119 2708 4.4
650.9 – 187 2708 6.9
Liu [21] 2007 – 480.4 > 150.0 108 1458 7.4 6
228.0 ≤ 150.0 22 1229 1.8
Tang [22] 2006 – 612.5 124.2 ± 88.2 141 1184 11.9 6
269.4 136.6 ± 89.2 95 889 10.7
642.9 183.0 ± 190.2 148 1133 13.1 6
244.5 124.1 ± 105.1 129 862 9.7
499.7 112.3 ± 85.3 114 1032 11.1
Jia [23] 2006 – 460.5 > 150.0 84 570 14.7
35 269 13.1
310.3 ≤ 150.0 60 656 9.1 6
23 316 7.3
Dai [24] 2013 2004–2010 433.3 – 55 211 26.1
296.1 – 16 235 6.8
313.9 – 20 216 9.3 7
345.9 – 19 208 9.1
199.8 – 14 237 5.9
– ≤ 100.0 91 247 36.8
– 100.0–200.0 573 2019 26.4
– 200.0–300.0 294 1189 24.7
– 300.0–400.0 205 648 31.6
– > 400.0 741 2230 33.2

Discussion
This study explored the relationship between high iodine
levels and the prevalence of goiter development through
a meta-analysis of the 10 cross-sectional studies, using
UIC and WIC as indicators of iodine exposure. For ethi-
cal reasons, it is difficult to conduct a randomized con-
trolled trial exploring the effects of high iodine exposure
on goiter development. Therefore, it was speculated that
the inclusion of cross-sectional studies in our meta-anal-
ysis might help to account for the association between
high iodine levels and goiter development among school
children.
UIC was the most common and practical marker used
to estimate population iodine levels and their iodine
intake [25, 26]. This is because > 90% of dietary iodine
is readily excreted in urine [27]. Using urinary iodine
levels as a marker for iodine exposure, it was found that
there was a higher prevalence of goiter development
in people with a high iodine intake (UIC ≥ 300 μg/L)
when compared to those with a normal and slightly
elevated intake (100 μg/L ≤ UIC < 300 μg/L). Moreover,
the linear trend analysis showed that the prevalence of
goiter development generally increased as iodine intake
increased.
Xu et al. Nutr Metab (Lond) (2021) 18:46
Fig. 2 A forest plot of results for a UIC ≥ 300 μg/L and the prevalence of goiters
Fig. 3 Forest plot of result of WIC ≥ 100 μg/L and the prevalence of goiters
Water is a key resource which people ingest every
day, if the concentration of iodine in the water is too
high, it will affect the levels of iodine in the human
body. After 2016, a WIC > 100 μg/L was defined as
high level of iodine in water (GB/T 19380-2016). In
this meta-analysis, it was found that when the WI was
greater than 100 mg/L, the OR of goiter development
was 4.47 (95% CI 1.15, 19.46, P < 0.001). Though the
results of the Jia Q Z, and Tang Z C’s study cross the
invalid line and lack statistical significance, the OR val-
ues of the remaining studies within the meta-analysis
were greater than 1; this suggests that high iodine levels
lead to an increased risk of goiter development.
A Goiter is the enlargement of the thyroid. There was
research found that excessive iodine intake will increase
the synthesis of thyroid hormones and change the anti-
genicity of thyroglobulin, leading to the accumulation
of colloid in the thyroid follicular cavity and flatten-
ing of thyroid follicular epithelial cells [28]. This is a
Page 6 of 9
typical pathological manifestation of goiter caused by
high iodine. The decrease in thyroid hormone production
caused by high iodine levels is called the Wolff-Chaik
off effect [29]. Normally, thyroid hormone levels return
to normal after a few days; this is termed the so-called
“escape” phenomenon [30]. Although the mechanism by
which high iodine causes goiter development remains
unclear, failure to “escape” is considered to play a role. In
addition, the continuous stimulation of thyroid stimulat-
ing antibodies activate NIS and/or spread lymphocyte
infiltration; this may also play a role in high iodine levels
causing the development of a goiter [31].
Clarifying the risk of high iodine on goiter develop-
ment has important clinical and public health signifi-
cance. Iodine is the main raw material in the synthesis of
thyroxin. Changes in environmental iodine levels directly
affect iodine intake; this in turn affects the subsequent
changes in the synthesis and secretion of thyroid hor-
mones. A study explored the effect of high parental
Xu et al. Nutr Metab (Lond) (2021) 18:46 Page 7 of 9

Fig. 4 Forest plot of subgroup analysis of results of a UIC ≥ 300 μg/L and the prevalence of goiters
Xu et al. Nutr Metab (Lond) (2021) 18:46
Table 2 mantel Haenszel χ2 test of UIC and goiter
UIC (μg/l) Goiter Not goiter χ2 P
100–300 3405 53,918 734.605
300–500 2499 24,157
500–800 1381 11,732
800––1000 182 1116
≥ 1000 310 1606
iodine levels on the thyroid hormone levels of offspring.
First, parental mice were dosed with iodine using tap
water containing iodine (3000 μg/L) for 4 months. At the
end of the fourth month, the mice were paired for mat-
ing. The levels of thyroid hormone and TSH in the serum
and brain of the offspring mice were then measured after
birth. It was found that on the 14th day post-birth, the
serum T4 level in the high iodine group was significantly
reduced, whilst the serum TSH was higher than that of
the control group [32]. Most healthy individuals can tol-
erate a high iodine intake. However, in certain suscep-
tible populations, an excessive iodine intake may lead
to hyperthyroidism [33], hypothyroidism [34], thyroid
enlargement [35] and thyroid autoimmunity [36].
Considering the difficulty of conducting randomized
trials and the absence of a meta-analysis of the relation-
ship between high iodine intake and the development
of a goiter, this study is of great significance for public
health managers. These results confirm the necessity
of monitoring iodine concentration in water and urine.
The development of a goiter is a sensitive marker that
reflects the long-term impact of a high iodine intake
effect; the prevalence of goiters within a population has
traditionally been a marker that reflects the long-term
iodine status of a population.
This meta-analysis had several advantages. Firstly,
this was the first meta-analysis assessing both UIC and
WIC as iodine exposure markers; it was also the first
which explored the risk of different high iodine levels
on goiter development. secondly, it further confirmed
that HUI and HWI can cause goiters, whilst also show-
ing that urinary iodine and water iodine levels can be
used as indicators of iodine exposure. Thirdly, in order
to ensure the research quality of this meta-analysis,
strict inclusion criteria were developed which helped to
increase the robustness of the data. Finally, an extensive
article retrieval and data extraction was conducted by
3 independent reviewers. At the same time, there are
several limitations to the review. The included stud-
ies were cross-sectional studies, so the study is unable
to determine causality between high iodine intake and
goiter development. Also, as there is only limited rel-
evant literatures for newborns, pregnant women, the
Page 8 of 9
elderly and other groups, only included school-age chil-
dren were investigated in this meta-analysis. Further
researches needed to be done to explore the relation-
< 0.001 ship between high iodine levels and goiter development
in newborns, pregnant women and the elderly.
Conclusions
In conclusion, the results of this meta-analysis showed
that HUI or HWI increase the risk of the development
of goiters. It also showed that as concentration of urinary
iodine or water increased; the risk of goiter increaed.
Abbreviations
USI: Universal salt iodization; HUI: High urinary iodine; HWI: High water iodine;
CNKI: China National Knowledge Infrastructure; UIC: Urinary Iodine concentra-
tion; WIC: Water iodine concentration; OR: Odds ratio; CI: Confidence interval.
Acknowledgements
Thanks to the National Natural Science Foundation of China for its financial
support; thanks to the Tianjin Medical University Library for providing a free
document retrieval platform; thanks to Tianjin Medical University School of
Public Health and Tianjin Key Laboratory of Environmental Nutrition and
Human Health for providing a good environment for paper retrieval and
writing.
Authors’ contributions
The authors’ responsibilities were as follows—LT: designed the research; TX:
performed the statistical analysis, conducted the meta-analysis and drafted
the paper; TX, ZR and SL: provided essential materials; WZ and LT: provided
comments and edits for the paper; TX, ZR and SL: had primary responsibility
for the final content. All authors read and approved the final manuscript.
Funding
Dr. Long-Tan was supported by grants from National Natural Science Founda-
tion of China (81703218, 82073549). Supported by the Tianjin Key Laboratory
of Environment, Nutrition and Public Health and the Center for International
Collaborative Research on Environment, Nutrition and Public Health.
Availability of data and materials
The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 12 October 2020 Accepted: 12 March 2021
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